Research Targets Bacteria Behind Hospital-associated Infections

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Kansas State University researchers are defeating persistent bacteria known for causing infections in hospitals.

The bacteria, Enterococcus faecalis, are the second-leading cause of hospital-associated infections in the U.S., said Lynn Hancock, associate professor of biology and leader of the research. His team
has discovered how a regulatory system helps this bacteria resist a
host's innate immune defense -- a finding that may help develop novel
drug compounds to fight the bacteria.

"Right now,
we have very limited therapeutic interventions because the bacteria is
highly resistant to not only antibiotics but a variety of other
environmental stresses," Hancock said. "With the diminishing number of
antibiotics that are effective at treating these types of infections, we
need to come up with new strategies."

Enterococcus
faecalis, or E. faecalis, is naturally found in the gastrointestinal
tract of humans and other mammals. But outside the intestinal walls, the
bacteria can cause bacteremia, urinary tract infections and
endocarditis.

An added obstacle is that the
bacteria are 100 to 1,000 times more resistant to lysozyme than other
bacteria, Hancock said. Lysozyme is an infection-fighting substance that
humans produce and is found in numerous body tissues, such as tear
film, the urinary tract and saliva. The regulatory system of E. faecalis
also makes it very resistant to other cellular stresses -- such as
elevated temperature, low pH and oxidative stress -- that are part of a
person's innate immune defense and help fight infection.

"Enterococcus
has evolved sensing systems to find out the kind of environment it is
in," said Sriram Varahan, doctoral student in microbiology and member of
Hancock's research team. "It is a really rugged bacteria that is known
to persist and survive in environments where other pathogens are unable
to do so. Many infectious disease specialists have given it the moniker
of being the cockroach of the microbial world."

By
understanding the bacteria's regulatory network, the researchers hope
to develop novel drug compounds that can block the bacterium's ability
to sense and respond to the presence of lysozyme and other stresses
during infection. To find the bacteria's weakness, the scientists
focused on a protein called Eep. While studies have shown that Eep is
important during infection, the Kansas State University researchers
discovered how Eep contributes to an important stress response that the
bacteria use to survive the host defense.

It is an
important finding because now researchers can develop compounds that
inhibit the Eep protein, which makes the bacteria susceptible to
lysozyme and stops infection. When humans produce lysozyme to fight the
bacteria, the bacteria will be unable to fight back.

"It's kind of like hitting it in the Achilles' heel," Hancock said. "Then it is very much compromised to establish infection."

While
the bacteria are still able to live without the Eep protein, the
bacteria need it to cause infection, Hancock said. Studies have shown
that when the Eep is inactivated, bacteria are compromised nearly
10,000-fold in their ability to cause infection.

"The
ability to interfere with a bacteria's ability to establish infection
is going to become a more popular theme for treating infections rather
than simply killing the bacteria," Hancock said. "When you put selective
pressure on bacterial populations to live or die, they are really good
at circumventing the drugs and getting around the killing mechanism."

For
future research, Hancock and his team want to find what compounds are
most effective at interfering with Eep to make the bacteria susceptible
to lysozyme. They also want to study the SigV protein, which coordinates
expression of target genes that are controlled by the Eep protein.
Similar to Eep, if SigV is inactivated, then the target genes are not
expressed and the bacteria do not become resistant to lysozyme. These
target genes and proteins may also lead to new drug development
possibilities.

"In the dawn of the post-antibiotic
era, I think it is essential for us to have more options, rather than
depending on a few silver bullets that are seemingly failing a lot in
hospitals nowadays," Varahan said. "We have come up with new targets and
hopefully they will work."

The scientists recently
published their research in the Journal of Bacteriology. The research
was part of a $1.5 million five-year grant from the National Institutes
of Health.

Other researchers involved include
Vijayalakshmi Iyer, research associate in biology, and William Moore, a
former doctoral student in microbiology.

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